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<p>Bruton’s tyrosine kinase inhibitors (BTKi), widely used in Waldenström macroglobulinemia (WM), are known to impair B cell function, but their broader immunological effects remain unclear. We investigated the T cell compartment in patients with WM receiving BTKi, including those who underwent a supervised treatment pause before a third COVID-19 mRNA vaccine dose, as well as treatment naïve controls. Using flow cytometry, antigen-specific T cell assays, and single-cell RNA sequencing, we found that BTKi-treated patients exhibited a reduction in naïve T cells, enrichment of terminal effector CD8⁺ T<sub>emra</sub> cells, and lower PD-1 expression. Despite poor vaccine-induced RBD-specific memory B cells, CD4⁺ and CD8⁺ T cell responses to SARS-CoV-2 remained detectable, with enhanced CD8⁺ responses to the omicron variant in BTKi-treated individuals. Single-cell transcriptomics revealed an expansion of CD16⁺ CD56⁺ Granzyme B⁺ NK-like CD8⁺ T cells in BTKi-treated patients, which further increased following BTKi interruption. These cells expressed a potent cytotoxic and NK-like transcriptional phenotype. Our findings identify a novel off-target effect of BTKi therapy: expansion of cytotoxic NK-like CD8⁺ T cells, with implications for immune monitoring and vaccine responsiveness in BTKi-treated patients.</p>

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Expanded CD16+CD56+Granzyme B+ NK like CD8+ T cells an off target effect of bruton’s tyrosine kinase inhibitors in Waldenström macroglobulinemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月5日

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  • Priyanka Hastak,
  • Chansavath Phetsouphanh,
  • Zong-Hong Zhang,
  • Rowena A. Bull,
  • Lok Bahadur Shrestha,
  • Vera Klemm,
  • Raymond Louie,
  • Fabio Luciani,
  • C. Mee Ling Munier,
  • Alexandra Carey Hoppé,
  • Elizabeth Keoshkerian,
  • Brendan Beaton,
  • Katherine Rankin,
  • Alexander Wong,
  • Judith Trotman,
  • Anthony D. Kelleher,
  • Sarah C. Sasson

摘要

Bruton’s tyrosine kinase inhibitors (BTKi), widely used in Waldenström macroglobulinemia (WM), are known to impair B cell function, but their broader immunological effects remain unclear. We investigated the T cell compartment in patients with WM receiving BTKi, including those who underwent a supervised treatment pause before a third COVID-19 mRNA vaccine dose, as well as treatment naïve controls. Using flow cytometry, antigen-specific T cell assays, and single-cell RNA sequencing, we found that BTKi-treated patients exhibited a reduction in naïve T cells, enrichment of terminal effector CD8⁺ Temra cells, and lower PD-1 expression. Despite poor vaccine-induced RBD-specific memory B cells, CD4⁺ and CD8⁺ T cell responses to SARS-CoV-2 remained detectable, with enhanced CD8⁺ responses to the omicron variant in BTKi-treated individuals. Single-cell transcriptomics revealed an expansion of CD16⁺ CD56⁺ Granzyme B⁺ NK-like CD8⁺ T cells in BTKi-treated patients, which further increased following BTKi interruption. These cells expressed a potent cytotoxic and NK-like transcriptional phenotype. Our findings identify a novel off-target effect of BTKi therapy: expansion of cytotoxic NK-like CD8⁺ T cells, with implications for immune monitoring and vaccine responsiveness in BTKi-treated patients.